Antibiotics Lecture 03

Bio 319: Antibiotics
Lecture Three
Topic: Inhibitors of cell wall synthesis (brief)
Inhibitors of protein biosynthesis

Lecturer: Dr. G. Kattam Maiyoh

13/02/2013 GKM/BIO319:Antibiotics/Lec. 03/Sem02/2013 1

Inhibitors of Cell Wall Synthesis


Carbapenems
• Beta-lactam ring is
fused to a 5 member
ring system
• Effect on microbes
and pharmacology
of carbapenems
similar to penicillins


Selected Carbapenems
• Imipenem
– Broad spectrum including anaerobes
and Pseudomonas aeruginosa
– Parentally administered
– Must be combined with cilastatin to be
absorbed
– Excreted by kidneys
• Meropenem, ertapenem, and doripenem
are similar to imipenem but don’t need co-
administration with cilastatin

cilastatin chemical compound which inhibits the human enzyme dehydropeptidase

Toxicity/Contraindications
of Carbapenems
• Nausea and vomiting (common)
• Hypersensitivity reactions (uncommon)
– Essentially the same as for penicillins, exception
is the monobactam
– Cross-reactivity is possible, exception is the
monobactam

GKM/BIO319:Antibiotics/Lec.
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Aztrenam – a monobactam
• Works only on Gm -ve, including Pseudomonas
aeruginosa
• Useful for treating G-ve infections that require
a beta-lactam because it does not elicit
hypersensitivity reactions

• Monobactam - beta-lactam compounds
wherein the beta-lactam ring is alone and not
fused to another ring

Beta-lactamase inhibitors
a. Clavulanic acid
– Irreversible inhibitor of β-lactamase
– Good oral absorption
– Combined with amoxicillin or ticarcillin

b. Sulbactam


Peptide Antibiotics
Peptide Antibiotics are drugs with
polypeptides structure
Sub-group of Peptide Antibiotics
Polymyxins
Glycopeptides
Bacitracin
Streptogramins

Each drug group has its own
mechanism of action
4 groups and 4 mechanism
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• Peptide antibiotics – May be
further classified as follows;
–Polymyxins
»Polymyxin B
»Colistin
–Glycopeptides
»Vancomycin
»Teicoplanin
»Avoparcin
–Bacitracin
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Polymyxins
Drug members
Polymyxin B
Colistin (Polymyxin E)
Mechanism of action
Detergent-like action
Damage to cell membrane function
Bind to LPS and destroy outer membrane
of Gram-negative bacteria
Bactericidal
Concentration-dependent
Non-selective on bacterial membrane
Spectrum of activity
Gram-negative bacteria
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Polymyxins
• Pharmacokinetics
– Not absorbed via GI tract
– If injection, drug accumulated and slowly
excreted
• Toxicities
– Highly toxic if systemic injection
– Nephrotoxic
– Neurotoxic
• Clinical uses
– Oral treatment
– Local treatment
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Glycopeptides
• Group members
– Vancomycin
• Antibacterial activity
– Inhibition of cell wall synthesis
– Active against Gram-positive bacteria
• Not absorbed orally, must administered IV
• High toxicity
– Local irritation , ototoxicity, nephrotoxicity
• Clinical uses
– Hardly used in animals
– Used only resistant case i.e. to beta-lactams

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Bacitracin
• Only member is Bacitracin
• Drug activity
– Inhibit cell wall synthesis
– Activity on Gram-positive bacteria
– Bactericidal
• Nephrotoxic if systemic injection
• Clinical uses – the same as polymyxin
– Oral – as growth promoter
– Local or topical drugs

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Antibiotics that Inhibit Protein Synthesis

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Protein synthesis inhibitors
– Aminoglycosides
– Tetracyclins
_Spectinomycin
– Macrolides
– Chloramphenicol
– Clindamycin

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Inhibition of Protein Synthesis by Antibiotics

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03/Sem02/2013 Figure 20.4

Review of Initiation of Protein Synthesis
1 3
30S 2 GTP

1 2 3 GTP
Initiation Factors
f-met-tRNA
mRNA
Spectinomycin

3

GDP + Pi
50S
2
P A
1 1
2 GTP

70S Aminoglycosides
30S
Initiation Initiation
Complex
13/02/2013
03/Sem02/2013 Complex 17

Review of Elongation of Protein Synthesis

P A Tetracycline P A

Tu GTP Tu GDP + Pi

GTP Ts
Ts Tu
Ts GDP
Chloramphenicol

GDP
Fusidic Acid +
GTP
G

G GDP + Pi
G GTP
P A P A

Erythromycin
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Survey of Antibiotics

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Protein Synthesis Inhibitors
• Mostly bacteriostatic
• Selectivity due to differences in prokaryotic
and eukaryotic ribosomes
• Some toxicity - eukaryotic 70S ribosomes


Antimicrobials that Bind to the 30S
Ribosomal Subunit

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a) Aminoglycosides (bactericidal)
streptomycin, kanamycin, gentamicin, tobramycin, amikacin,
netilmicin, neomycin (topical)
• Mode of action - The aminoglycosides irreversibly bind
to the 16S ribosomal RNA and freeze the 30S initiation
complex (30S-mRNA-tRNA) so that no further initiation
can occur.
• They also slow down protein synthesis that has already
initiated and induce misreading of the mRNA.
– By binding to the 16 S r-RNA the aminoglycosides increase
the affinity of the A site for t-RNA regardless of the anticodon
specificity.
• May also destabilize bacterial membranes.
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Microbe Library
American Society for Microbiology
www.microbelibrary.org
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b) Aminoglycosides (bactericidal)
streptomycin, kanamycin, gentamicin, tobramycin, amikacin,
netilmicin, neomycin (topical)

• Spectrum of Activity –Effective against many gram-
negative and some gram-positive bacteria;
• Not useful for anaerobic (oxygen required for uptake of
antibiotic) or intracellular bacteria.
• Resistance - Common
• Synergy - The aminoglycosides synergize with β -lactam
antibiotics. The β -lactams inhibit cell wall synthesis and
thereby increase the permeability of the aminoglycosides.


c) Tetracyclines (bacteriostatic)
tetracycline, minocycline and doxycycline

• Mode of action - The tetracyclines reversibly bind to the 30S
ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site
on the 70S ribosome.

• Spectrum of activity - Broad spectrum; Useful against intracellular
bacteria


• Adverse effects - Destruction of normal intestinal flora resulting in
increased secondary infections; staining and impairment of the
structure of bone and teeth.

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d) Spectinomycin (bacteriostatic)
• Mode of action - Spectinomycin reversibly interferes with m-RNA
interaction with the 30S ribosome. It is structurally similar to the
aminoglycosides but does not cause misreading of mRNA.

• Spectrum of activity - Used in the treatment of penicillin-resistant
Neisseria gonorrhoeae

• Resistance - Rare in Neisseria gonorrhoeae

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Antimicrobials that Bind to the 50S
Ribosomal Subunit

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a) Chloramphenicol, Lincomycin,
Clindamycin (bacteriostatic)
• Mode of action - These antimicrobials bind to the 50S ribosome and
inhibit peptidyl transferase activity.

• Spectrum of activity - Chloramphenicol - Broad range;
Lincomycin and clindamycin - Restricted range


• Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but
is used in the treatment of bacterial meningitis.

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b) Macrolides (bacteriostatic)
erythromycin, clarithromycin, azithromycin, spiramycin

• Mode of action - The macrolides inhibit translocation.

• Spectrum of activity - Gram-positive bacteria,
Mycoplasma, Legionella


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Macrolides : Classification
• Macrolides are drugs with lactone ring
structure
• Sub-groups are based on no. of ring atom
– 12-membered ring macrolides
– 13-membered
– 14-membered (many drugs)
– 15-membered
– 16-membered (many drugs)
• Special groups
– Azalides – name for 15-membered
– Triamilides – name for tulathromycin
(combination of 13- and 15-membered)
– Ketolides – name for 14-membered with 3
keto group

Macrolides
Drug examples
13-membered
Tulathromycin (Triamilides)
14-membered
Erythromycin
Clarithromycin, Roxithromycin,
Dirithromycin
15-membered
Azithromycin (Azalides)
Tulathromycin (Triamilides)
16-membered
Spiramycin
Tylosin

Macrolides – general
properties
• Mechanism of
action
– Inhibit protein
synthesis
– Bind to 50S
ribosomal unit
– Bacteriostatic
• Spectrum of
activity
– Gram-positive
– Some Gram-
negative

Macrolides
Pharmacokinetics
Broad distribution in body
tissues
High intracellular
concentration

Macrolides
Additional properties
of Macrolides
• Anti-inflammatory
effect
– Inhibitory effect on
neutrophils
– inhibit
proinflammatory
cytokines
– Useful for treatment
of inflammatory

Erythromycin
• Erythromycin is a standard or basic drug of
macrolides
• Other drug members are usually compared
with erythromycin
• Important adverse effect - severe diarrhea
– Especially in adult horse and ruminants
• Clinical uses
– Second choice (alternative drug)
– Small animals
– Fowls
– Some cases in ruminants
– Not used in pigs

Tylosin and Spiramycin
• Tylosin and Spiramycin
– Activities are similar
to erythromycin
– Good activity on
Mycoplasma
• Clinical uses
– Macrolides used in
ruminants and pigs
– Used for Mycoplasma
infection

Advanced generation
Macrolides
Example drugs
Roxithromycin
Dirithromycin
Clarithromycin
Azithromycin
General activity – the same as erythromycin
Better Pharmacokinetic properties
Acid stable
Fewer GI side effect
Higher oral availability
Longer serum half-lives
Higher tissue concentrations

Ketolides
• Ketolides are 14-
membered ring
macrolides with 3
keto group
• Specific drugs
– Telithromycin
– Cethromycin (still
in clinical study)
• Important
properties
– Less resistance
– Good activities on

Antimicrobials that Interfere with
Elongation Factors

Selectivity due to differences in prokaryotic and eukaryotic
elongation factors

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Fusidic acid (bacteriostatic)
• Mode of action - Fusidic acid binds to elongation factor G (EF-G) and
inhibits release of EF-G from the EF-G/GDP complex.

• Spectrum of activity - Gram-positive cocci


Antibiotics Lecture 03

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